PROJECT SUMMARY Myocardial infarction and hypertrophic cardiomyopathy followed by heart failure is a major cause of death worldwide. As the terminally differentiated adult cardiomyocytes possess a very limited innate ability to regenerate, much research has focussed on exploring the potential of adult stem cells and induced pluripotent stem cells to repair the damaged myocardium. However with regards to benefits till date, experimental and clinical trials have shown sub-optimal to modest results. The main drawback for this is that the mechanisms involved for the in vivo therapy is not well understood. Suggested pathways include permanent or partial cell fusion between stem cells and resident cardiac cells, transdifferentiation of stem cells into cardiac and vascular cells and secretion of proangiogenic paracrine factors. However, none of them have considered the fact that the dynamic cardiac microenvironment can also induce significant biological effects on the transplanted stem cells that can influence their overall fate and functionality. In this project we will study, for the first time, the fundamental microenvironmental interactions between mesenchymal stem cells and contractile cardiomyocytes in a continuously beating 3D microenvironment that can influence the clinical outcomes when transplanted in patients with cardiomyopathy. Furthermore, we will also study the potential of the mechano-biologically activated stem cells, pre-conditioned in this 3D cardiac microenvironment, for myocardial regeneration therapy in animal model. Established collaborations with members (physicians and scientists) from the Midwest Stem Cell Therapy Center (MSCTC) at KU Medical Center, The KU Center for Epigenetics and Stem Cell Biology (CESCB), KU Center for Molecular Analysis of Disease Pathways (CMADP) and University of Cincinnati Cardiovascular Disease Center will provide further support and guidance to successfully pursue the project.